Synthesis of 6,7,8-trisubstituted purines via a copper-catalyzed amidation reaction

Article abstract of DOI:10.1021/jo802248g

(Chemical Equation Presented) We report herein an efficient method for the synthesis of 6,7,8-trisubstituted purines via a copper-catalyzed amidation reaction from easily accessible starting materials. Furthermore, the resulting 6-benzylsulfanyl-substitut

Full text of DOI:10.1021/jo802248g

SCHEME 1. Known Approaches to the Syntheses of the
Synthesis of 6,7,8-Trisubstituted Purines via a
Copper-Catalyzed Amidation Reaction
N-Alkyl and N-Arylbenzimidazolesa
Nada Ibrahim and Michel Legraverend*
UMR 176, Institut Curie, Baˆt. 110-112, Centre UniVersitaire,
91405 Orsay, France
michel.legraVerend@curie.u-psud.fr
ReceiVed October 08, 2008
a Reagents and conditionssMethod A: (1) Cu/L-proline/K2CO3, DMSO,
rt-50 °C; (2) heat or AcOH, 40-60 °C, 61-97%. Method B: (1) CuI,
Cs2CO3, DMF, rt; (2) AcOH, 50 °C (without a ligand), 82% only with R1
) CF3. Method C: (1) CuI/L, Cs2CO3, 1,4-dioxane, 90 °C, 2 h; (2) K3PO4,
t-BuOH, 110 °C or AcOH 75 °C, 72-82%.
This was indeed the case in all our attempts to apply this
method to introduce more complex substituents at position 8.
Although other methods exist for the preparation of purine
derivatives, e.g., from 8-halogenopurines,9-12 or by direct
arylation at C-8,13,14 we wanted to develop a more general
method that could lead to a variety of 6,7,8-trisubstituted purines
in high yield.
Our attention was drawn by the recent work by Ma and co-
workers,15 who described a Cu-catalyzed aryl amination/
condensation process, using 2-iodoacetanilides 1, which led to
a series of 1,2-disubstituted benzimidazoles 4 in high yield
(method A). Buchwald simultaneously reported16,17 a similar
copper-catalyzed amination/cyclization of related acetanilide
(Scheme 1, R1 ) CF3), but unfortunately, the process lacked
generality (method B).
Interestingly, Buchwald developped an improved method
involving a copper-catalyzed amidation of a 2-iodoaniline 216
in the presence of a diamine ligand, which led to various
N-alkyl-2-substituted benzimidazoles 4 in good yields (Method
C) (68-93%).
In view of the potential generality of these syntheses of
benzimidazoles, we wanted to investigate the use of this strategy
in the synthesis of 6,7,8-trisubstituted purines (Scheme 2). In
this Note, we report a new efficient method for the three-step
synthesis of 6,7,8-trisubstituted purines from a suitable pyri-
midine precursor, using a copper-catalyzed amidation.
For this purpose, we required a functionality in the final purine
derivative which would allow the introduction of various
substituents at position 6. However, our first attempts with 4,6-
dihalogenopyrimidines met with little success. When 5-amino-
We report herein an efficient method for the synthesis of
6,7,8-trisubstituted purines via a copper-catalyzed amidation
reaction from easily accessible starting materials. Further-
more, the resulting 6-benzylsulfanyl-substituted purine de-
rivatives may be readily oxidized for substitution by nucleo-
philes to give access to 6,7,8- trisubstituted purines for
biological screening purposes.
The purine core is a privileged scaffold in medicinal chemistry
that is frequently used in the preparation of combinatorial
libraries.1,2 Its seven peripheral atoms may be considered as
seven potential points of structural diversity, and a wide variety
of interesting inhibitors and modulators of key biological targets
have been found among derivatives bearing various combina-
tions of substituents at these centers.3
Various methodologies have been developed for the synthesis
of polysubstituted purines,4-7 but some derivatives bearing an aryl
or a heteroaryl substituent at position 8 are more difficult to obtain.
For example, 2,6,8,9-tetrasubstituted purines can be prepared from
6-chloro-2-alkyl (or 2-aryl)-4,5-diaminopyrimidine precursors by
treatement with an alkyl (or aryl) aldehyde or carboxylic acid, but
the yield of the resulting 6-chloro-2,8,9-trisubstituted purine is low,
due to hydrolysis of the chlorine atom.8
(1) Ertl, P.; Jelfs, S.; Mu¨hlbacher, J.; Schuffenhauer, A.; Selzer, P. J. Med.
Chem. 2006, 49, 4568–4573.
(2) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893–930.
(9) Capek, P.; Vra´bel, M.; Hasn´ık, Z.; Pohl, R.; Hocek, M. Synthesis 2006,
3515–3526.
(3) Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987–
4006.
(4) Hammarstrom, L. G. J.; Smith, D. B.; Talamas, F. X. Tetrahedron Lett.
2007, 48, 2823–2827.
(10) Collier, A.; Wagner, G. Org. Biomol. Chem. 2006, 4, 4526–4532.
(11) Havelkova, M.; Dvorak, D.; Hocek, M. Synthesis 2001, 1704–1710.
(12) Vrabel, M.; Pohl, R.; Klepetarova, B.; Votruba, I.; Hocek, M. Org.
Biomol. Chem. 2007, 5, 2849–2857.
(5) Elzein, E.; Kalla, R.; Li, X.; Perry, T.; Parkhill, E. Bioorg. Med. Chem.
Lett. 2006, 16, 302–306.
(6) Zablocki, J.; Kalla, R.; Perry, T.; Palle, V.; Varkhedkar, V. Bioorg. Med.
Chem. Lett. 2005, 15, 609–612.
(7) Legraverend, M. Tetrahedron 2008, 64, 8585–8603.
(8) (a) Yang, J.; Dang, Q.; Liu, J.; Wei, Z.; Wu, J.; et al. J. Comb. Chem.
2005, 7, 474–482. (b) Liu, J.; Dang, Q.; Wei, Z.; Shi, F.; Bai, X. J. Comb.
Chem. 2006, 8, 410–416.
(13) Cerna, I.; Pohl, R.; Hocek, M. Chem. Commun. 2007, 4729–4730.
(14) Cerna, I.; Pohl, R.; Klepetarova, B.; Hocek, M. Org. Lett. 2006, 8, 5389–
5392.
(15) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. Engl. 2007, 46, 2598–
2601.
(16) Zheng, N.; Buchwald, S. L. Org. Lett. 2007, 9, 4749–4751.
(17) Zheng, N.; Anderson, K. W.; Huang, X.; Nguyen, H. N.; Buchwald,
S. L. A. Angew. Chem., Int. Ed. Engl. 2007, 46, 7509–7512.
10.1021/jo802248g CCC: $40.75
Published on Web 11/14/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 463–465 463

TABLE 1. Scope for Copper-Catalyzed Synthesis of Various
8-Aryl(Bu)-6,7-Substituted Purine Derivatives 15a-n
SCHEME 2. Synthesis of 6,8-Disubstituted Purines
entry
compd
R1
yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15a
15b
15c
15d
15e
15f
15g
15h
15i
15j
15k
15l
15m
15n
Ph
53
68
75
65
66
61
68
75
67
70
73
80
75
45
3-Cl-Ph
4-Cl-Ph
4-MeO-Ph
4-pyridyl
3-pyridyl
3-NO2-Ph
4-NO2-Ph
3-F-Ph
4-F-Ph
2-F-Ph
2-tolyl
3-MeO-Ph
n-butyl
4,6-dichloropyrimidine 5 was treated with CuI (10 mol %) and
ligand L (40 mol %) in the presence of benzamide, no purine
8a was formed (Scheme 2) and significant degradation of the
starting material was observed. In the case of 5-amino-4,6-
diiodopyrimidine18 6 a very low yield (<5%) of 6-iodopurine
8b (Scheme 2) was obtained, even when the amount of copper
and ligand (trans-N,N′-dimethylcyclohexane-1,2-diamine) was
increased. Experiments with Pd(0) catalyst19 instead of CuI gave
also the cyclization product 8b in very low yield and required
a much longer reaction time in a sealed vessel. Therefore we
returned to the CuI/ligand amidation conditions of Buchwald16
that we applied to the monoiodopyrimidine (9), to avoid any
diamidation. The choice to substitute one iodo atom in 6 by a
benzylsulfanyl group to give 9 was made first for the well-
known chemical stability of the benzylthioether under various
conditions (SNAr, Pd(0) cross-coupling), and second because
it can be activated to the sulfone for subsequent substitution by
nucleophiles. Thus, treatment of 5-amino-4-benzylsulfanyl-6-
iodopyrimidine (9) with 4-chlorobenzamide in the presence of
CuI and diamine ligand led to a small amount of purine 13
(16%) as well as a small quantity of pyrimidine 11a (18%)
(Scheme 2). In the case of 4-nitrobenzamide, purine 14 was
obtained in low yield (17%) and no pyrimidine intermediate
11b was detected in the reaction mixture (Scheme 2). In
addition, 9 treated with benzamide, in the presence of CuI/
ligand, remained unchanged (12 was not detected) (Scheme 2).
However, we were delighted to observe that a pure product
was obtained in 53% yield when the copper-catalyzed amidation
reaction was applied to a benzylsulfanyl pyrimidine precursor
10, in which the 5-amino group was methylated (Table 1, entry
1) (see the Supporting Information for the synthesis of 10 from
7, which was itself prepared by treating 6 with NaH followed
by MeI). The amounts of CuI (10 mol %) and ligand (40 mol
%) were optimized in the reaction of benzamide with 10, heating
for 24 h in a sealed tube (Table 1, entry 1). Further increase of
CuI led to some degradation and a higher amount of reduced
product 16. The best results were obtained with 1.5 equiv of
benzamide, in the presence of 2 equiv of Cs2CO3 at 90 °C. No
purine was formed in the absence of ligand.
a Isolated yields.
The coupling reaction of an alkyl amide was also carried out
and led to 8-butyl-substituted purine 15n in moderate yield
(45%).
The total conversion of pyrimidine 10 to purines 15 was
achieved in 7 h with all amides with the exception of benzamide,
nicotinamide, ortho-substituted benzamides (2-fluorobenzamide
and o-toluamide), and valeramide which required prolonged
reaction time (24 h) (Table 1, entries 1, 11, 12, and 14).
In contrast to the synthesis of N-alkylbenzimidazoles (Scheme
1, method C)16 the presumed pyrimidine intermediates (such
as 11) were not isolated and cyclized spontaneously by
dehydration to purine derivatives 15a-n (Table 1). A trace
amount (<5%) of reduced product 16 could be detected in all
of these experiments and was characterized by LC-MS and by
comparison to an authentic sample prepared from iodo derivative
10 by treatement with n-BuLi at -78 °C, followed by quenching
with H2O.
The utility of the 6-benzylsulfanyl group lies in its stability
under the amidation conditions and easy oxidation with m-
chloroperbenzoic acid to the corresponding sulfone for substitu-
tion with suitable nucleophiles.20,21 Examples of 6,7,8-
trisubstituted purines 18a-f bearing amino substituents at
position 6 were synthesized by heating the sulfone intermediate
17 in BuOH or THF in the presence of three different amines
(Scheme 3).
In conclusion, this method provides a new practical three-
step synthesis of 6,7,8-trisubstituted purines from a readily
available pyrimidine starting material. It utilizes a key amidation/
cyclization step with copper catalyst and diamine ligand (trans-
N,N′-dimethylcyclohexane-1,2-diamine) and avoids expensive
palladium catalysts and phosphine ligands. In addition, as shown
previously,20,21 the presence of a 6-benzylsulfanyl group in
compounds 10 or 15 opens the way to solid-phase synthesis of
6,7,8-substituted purines, using a sulfur-linked Merrifield resin
As shown in Table 1 this method was equally efficient with
electron-rich and electron-deficient aryl amides, suggesting that
the substrate scope for this method is high. A variety of
8-arylpurines 15a-m were thus obtained in 53-80% yields.
(18) Gomtsyan, A.; Didomenico, S.; Lee, C.-H.; Matulenko, M. A.; Kim,
K. J. Med. Chem. 2002, 45, 3639–3648.
(19) For examples of intermolecular cross-coupling between aryl halides and
amides using Xantphos/Pd(0) catalyst, see: (a) Yin, J.; Buchwald, L. Org. Lett.
2000, 2, 1101–1104. (b) Yin, J; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
6043–6048. (c) Dallas, A.; Gothelf, K. V. J. Org. Chem. 2005, 70, 3321–3323.
(d) Piguel, S.; Legraverend, M. J. Org. Chem. 2007, 72, 7026–7029.
(20) Brun, V.; Legraverend, M.; Grierson, D. S. Tetrahedron 2002, 58, 7911–
7923.
(21) Brun, V.; Legraverend, M.; Grierson, D. S. Tetrahedron Lett. 2001, 42,
8165–8167.
464 J. Org. Chem. Vol. 74, No. 1, 2009

SCHEME 3. Substitution of the 6-Benzylsulfanyl Group by
Amine Nucleophiles Following Sulfur Oxidation
mL) was stirred for 7 h at 90 °C (procedure A). After workup, the
residue was purified by flash chromatography on silica gel eluting
with dichloromethane/ethanol (gradient elution 100/0, and then 98/
2) to afford 15c as a white solid (yield 75%). Mp 202-203 °C; 1H
NMR (300 MHz, CDCl3) δ (8.89, s, 1H), 7.7 (d, J ) 6 Hz, 2H),
7.52 (d, J ) 9 Hz, 2H), 7.45 (d, J ) 9 Hz, 2H), 7.3 (m, 3H), 4.7
(s, 2H), 4.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.7, 152.8,
152.7, 137.3, 136.8, 131.1, 129.3, 128.7, 127.6, 127.0, 34.9, 33.5;
MS (electrospray) m/z (%), 389.0 (100) [M + Na]+, 367,0 (70)
[M + H]+. Anal. Calcd for C19H15ClN4S: C, 62.2; H, 4.12; N, 15.27.
Found: C, 61.84; H, 4.01; N, 15.19.
General Procedure
B
for the Preparation of
6-Aminopurines. A solution of commercial m-chloroperbenzoic
acid (3 equiv) in CH2Cl2 (10 mL) was dried over MgSO4 and added
dropwise to the corresponding compounds (6-benzylthio-7,8-
disubstitued purines) in CH2Cl2 at 0 °C, and the resulting mixture
was stirred for 8 h in an ice water-bath until disappearence of the
starting material as judged by TLC on silica gel in DCM/EtOH
5%. A saturated solution of Ca(OH)2 was added and after workup
(extraction with CH2Cl2, water washing, and MgSO4 drying of the
organic layer), the residue was evaporated under reduced pressure.
Compounds were sufficiently pure to be used directly in the next
step. The resulting sulfone and 1-2 equiv of the appropriate amine
in butyl alcohol (except for compound 18a where butyl alcohol
was replaced by THF) were heated at 110 °C for 4-48 h. After
evaporation, the residue was purified by flash chromatography on
silica gel (CH2Cl2/EtOH 0-6%).
Benzyl-[8-(4-methoxyphenyl)-7-methyl-7H-purin-6-yl]amine
(18a). 18a was synthesized according to procedure B as a white
solid that was recrystallized from EtOH in 69% yield. Mp 227-228
°C; 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 7.65 (d, J ) 9 Hz,
2H), 7.37 (m, 5H), 7.02 (d, J ) 9 Hz), 5.26 (t br, J ) 6 Hz), 4.855
(d, J ) 3 Hz), 4.01 (s, 3H), 3.88 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 161.7, 159.5, 156.0, 153.8, 151.0, 139.0, 131.7, 129.3,
128.3, 128.1, 121.4, 114.7, 55.8, 45.5, 34.8; MS (electrospray) m/z
(%), 368.1 (100) [M + Na]+, 346.2 (70), [M + H]+. HRMS (ESI)
calcd for C20H19N5O [MH+] 346.1668, Found 346.1665.
as a traceless linker. The synthesis reported here has the potential
to increase the diversity of the substituents that can be introduced
at position 8 for biological screening purposes. We expect it
will become a valuable addition to the methods available for
the synthesis of combinatorial libraries of purines.
Experimental Section
General Procedure A for the Copper-Catalyzed Couplings
of (4-Benzylsulfanyl-6-iodopyrimidin-5-yl)methylamine and
Amides. An oven-dried Schlenk was charged with 1 equiv of 10
(100 mg), the corresponding amide (1.5 equiv), cesium carbonate
(2 equiv), CuI (0.1 equiv, 10 mol %), (trans-N,N′-dimethylcyclo-
hexane-1,2-diamine, L) (0.4 equiv, 40 mol %), and degassed
dioxane (1.5 mL). The Schlenk was capped with a rubber septum
evacuated and backfilled with argon three times, the rubber septum
was replaced with a screwcap, and the mixture was stirred for 7-8
h (unless otherwise mentioned) at 90 °C. The reaction mixture was
allowed to cool to room temperature, diluted with dichloromethane
and water, and then extracted twice with dichloromethane. The
organic layers were combined dried with MgSO4 and then
concentrated under vacum. The crude material was purified by flash
chromatography on silica gel eluting with a gradient of ethanol in
dichloromethane.
6-Benzylsulfanyl-8-(3-chlorophenyl)-7-methyl-7H-purine
(15b). A mixture of 10 (100 mg, 0.28 mmol), 3-chlorobenzamide
(65.11 mg, 0.41 mmol), Cs2CO3 (187 mg, 0.57 mmol), CuI (5.3
mg, 0.027 mmol), L (15.78 mg, 0.11 mmol), and dioxane (1.5 mL)
was stirred for 7 h at 90 °C (procedure A). After workup, the residue
was purified by flash chromatography on silica gel (CH2Cl2/EtOH
2%) to afford 15b as a white solid (yield 68%): mp 161-162 °C;
1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 7.77 (s,1H), 7.64 (d,
J ) 6 Hz, 1H), 7.48 (m, 7.48, 4H), 7.34 (m, 3H), 4.71 (s, 2H),
4.11 (s,1H); 13C NMR (75 MHz, CDCl3) δ 158.0, 153.4, 137.2,
135.4, 131.4, 130.7, 130.6, 130.3, 129.1, 128.3, 128.1, 35.3, 33.9;
MS (electrospray) m/z (%), 389.0 (100) [M + Na]+. Anal. Calcd
for C19H15ClN4S: C, 62.2; H, 4.12; N, 15.27. Found: C, 61.92; H,
4.17; N, 15.21.
8-(4-Chlorophenyl)-7-methyl-6-pyrrolidin-1-yl-7H-purine
(18d). Procedure B gave a white solid that was recrystallized from
heptane/CH2Cl2 in 80% of yield. Mp 212-213 °C; 1H NMR (300
MHz, CDCl3) δ 8.52 (s, 1H), 7.78 (d, J ) 9 Hz, 2H), 7.52 (d, J )
9 Hz, 2H), 3.49 (s, 3H), 3.79 (m, 4H), 2.02 (m, 4H); 13C NMR (75
MHz, CDCl3) δ 160.6, 156.9, 153.0, 152.9, 137.3, 131.6, 129.5,
128.0, 117.0, 50.8, 37.9, 26.0; MS (electrospray) m/z (%), 314.2
(40) [M + H]+, 336.1 (100), [M + Na]+; HRMS (ESI) calcd for
C16H16N5Cl [MH+] 314.1172, Found 314.1168.
Acknowledgement. We thank Institut Curie for a doctoral
fellowship (N.I.) and Dr. Jason Martin for proofreading this
manuscript.
Supporting Information Available: Experimental proce-
dures and spectral data for compounds 6, 7, 9, 10, 11a, 13, 14,
15a, 15d-n, 16, 18b,c, and 18e,f. This material is available
free of charge via the Internet at http://pubs.acs.org.
6-Benzylsulfanyl-8-(4-chlorophenyl)-7-methyl-7H-purine
(15c). A mixture of 10 (100 mg, 0.28 mmol), 4-chlorobenzamide
(65.11 mg, 0.41 mmol), Cs2CO3 (187 mg, 0.57 mmol), CuI (5.3
mg, 0.027mmol), and L (15.78 mg, 0.11 mmol) in dioxane (1.5
JO802248G
J. Org. Chem. Vol. 74, No. 1, 2009 465